Therapeutics
In AF, apixaban reduced stroke or systemic embolism compared with warfarin, regardless of patient age
Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J. 2014;Feb 20 [Epub ahead of print].
Clinical impact ratings: F ★★★★★★✩ h ★★★★★★✩ C ★★★★★✩✩ H ★★★★★★✩ N ★★★★★★★★ Question In patients with atrial fibrillation (AF), does the efficacy and safety of apixaban compared with warfarin differ by patient age?
Methods Design: Prespecified subgroup analysis of a randomized controlled trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE] trial). ClinicalTrials.gov NCT00412984. Allocation: Concealed.* Blinding: Blinded* {patients, clinicians, outcome assessors, data collectors, and data analysts}†. Follow-up period: Median 1.8 years. Setting: 1034 centers in 39 countries. Patients: 18 201 patients (65% men; {median age 70 y}†, 30% < 65 y, 39% 65 to < 75 y, and 31% ≥ 75 y) who had AF or atrial flutter and ≥ 1 of cardiac failure, hypertension, age ≥ 75 years, diabetes, and previous stroke or transient ischemic attack. Exclusion criteria included previous intracerebral hemorrhage or stroke in the past 7 days, use of aspirin plus clopidogrel at study entry, or {need for anticoagulation for a cause other than AF}†. Intervention: Apixaban, 5 mg twice daily, {plus warfarin placebo (n = 9120)}†, or warfarin adjusted to achieve a target international normalized ratio of 2.0 to 3.0, {plus apixaban placebo (n = 9081)}†. Apixaban dose was reduced to 2.5 mg twice daily in patients with ≥ 2 of age ≥ 80 years, weight ≤ 60 kg, and serum creatinine level ≥ 133 µmol/L (≥ 1.5 mg/dL). Outcomes: Primary efficacy outcome was a composite of stroke or systemic embolism. Other outcomes included major bleeding and all-cause mortality. Patient follow-up: {97.9% for vital status}† (intention-to-treat analysis).
Main results {Overall, apixaban reduced stroke or systemic embolism, all-cause mortality, and major bleeding compared with warfarin.}† All outApixaban vs warfarin in atrial fibrillation‡ Outcomes Stroke or systemic embolism
Major bleeding
All-cause mortality
Age group
Event rates (%/y) Apixaban Warfarin
comes increased with patient age; the benefits of apixaban compared with warfarin did not differ by patient age group (Table).
Conclusion In patients with atrial fibrillation, apixaban reduced stroke or systemic embolism, all-cause mortality, and major bleeding compared with warfarin, regardless of patient age. *See Glossary. †Apixaban reduced stroke and systemic embolism compared with warfarin in atrial fibrillation [Abstract]. Ann Intern Med. 2012;156:JC1-2. Abstract of: Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92.
Sources of funding: Bristol-Myers Squibb and Pfizer. For correspondence: Dr. S. Halvorsen, Oslo University Hospital, Oslo, Norway. E-mail [email protected]. ■
Commentary Elderly persons are more likely to have AF, strokes in the setting of AF, and bleeding during anticoagulation therapy (1). Studies show consistently low rates of anticoagulation in the elderly, and although difficulties in monitoring and uncertainties about efficacy may explain underuse of anticoagulants, fear of hemorrhage seems to be an important factor (2). Halvorsen and colleagues found that the benefits of apixaban over warfarin for efficacy and safety are not affected by age. This finding should allay physician concerns about use of apixaban in older patients. What can we say about other non–vitamin K oral anticoagulants? Bleeding risk increased with age for both rivaroxaban and warfarin in ROCKET-AF, but risks were similar for each treatment across age strata (3). In RE-LY, patients ≥ 75 years of age had similar rates of extracranial bleeding with dabigatran, 110 mg twice daily, and a trend toward higher risk for major bleeding with dabigatran, 150 mg twice daily, compared with warfarin. Intracranial bleeding was reduced with both doses of dabigatran in all age groups (4).
Non–vitamin K oral anticoagulants have advantages in older persons, including ease of use and a lower risk for intracranial hemorrhage. Physicians should evaluate patient comorbid conditions, At a median 1.8 y concomitant medications, and cognition to RRI/RRR (95% CI)§ NNT (CI) minimize bleeding risks.
< 65 y
1.00%
0.86%
RRI 16% (−23 to 72)
Not significant
65 to < 75 y
1.25%
1.73%
RRR 28% (4 to 46)
114 (69 to 797)
≥ 75 y
1.56%
2.19%
RRR 29% (5 to 47)
< 65 y
1.17%
1.51%
RRR 22% (−11 to 45)
Not significant
65 to < 75 y
1.99%
2.82%
RRR 29% (11 to 43)
75 (49 to 196)
≥ 75 y
3.33%
5.19%
RRR 35% (20 to 47)
36 (27 to 62)
< 65 y
2.74%
2.56%
65 to < 75 y
2.67%
3.46%
≥ 75 y
5.42%
5.97%
RRI 6.8% (−16 to 34) RRR 22% (6 to 35) RRR 8.5% (−7 to 22)
91 (56 to 530)
Not significant 69 (44 to 264) Not significant
‡Abbreviations defined in Glossary. RRI, RRR, NNT, and CI calculated from hazard ratios and control event rates in article or provided by author. §Treatment by continuous age interaction: stroke or systemic embolism, P = 0.11; major bleeding, P = 0.63; and all-cause mortality, P = 0.43.
17 June 2014 | ACP Journal Club | Volume 160 • Number 12
Mukul Sharma, MD Kanjana Perera, MD McMaster University Hamilton, Ontario, Canada References 1. Sellers MB, Newby LK. Am Heart J. 2011;161: 241-6. 2. Gross CP, Vogel EW, Dhond AJ, et al. Clin Ther. 2003;25:1750-64. 3. Goodman SG, Wojdyla DM, Piccini JP, et al; ROCKET AF Investigators. J Am Coll Cardiol. 2014;63:891-900. 4. Eikelboom JW, Wallentin L, Connolly SJ, et al. Circulation. 2011;123:2363-72.
© 2014 American College of Physicians
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930364/ by a Tufts University User on 07/28/2017
JC7
In AF, apixaban reduced stroke or systemic embolism compared with warfarin, regardless of patient age
Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J. 2014;Feb 20 [Epub ahead of print].
Clinical impact ratings: F ★★★★★★✩ h ★★★★★★✩ C ★★★★★✩✩ H ★★★★★★✩ N ★★★★★★★★ Question In patients with atrial fibrillation (AF), does the efficacy and safety of apixaban compared with warfarin differ by patient age?
Methods Design: Prespecified subgroup analysis of a randomized controlled trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE] trial). ClinicalTrials.gov NCT00412984. Allocation: Concealed.* Blinding: Blinded* {patients, clinicians, outcome assessors, data collectors, and data analysts}†. Follow-up period: Median 1.8 years. Setting: 1034 centers in 39 countries. Patients: 18 201 patients (65% men; {median age 70 y}†, 30% < 65 y, 39% 65 to < 75 y, and 31% ≥ 75 y) who had AF or atrial flutter and ≥ 1 of cardiac failure, hypertension, age ≥ 75 years, diabetes, and previous stroke or transient ischemic attack. Exclusion criteria included previous intracerebral hemorrhage or stroke in the past 7 days, use of aspirin plus clopidogrel at study entry, or {need for anticoagulation for a cause other than AF}†. Intervention: Apixaban, 5 mg twice daily, {plus warfarin placebo (n = 9120)}†, or warfarin adjusted to achieve a target international normalized ratio of 2.0 to 3.0, {plus apixaban placebo (n = 9081)}†. Apixaban dose was reduced to 2.5 mg twice daily in patients with ≥ 2 of age ≥ 80 years, weight ≤ 60 kg, and serum creatinine level ≥ 133 µmol/L (≥ 1.5 mg/dL). Outcomes: Primary efficacy outcome was a composite of stroke or systemic embolism. Other outcomes included major bleeding and all-cause mortality. Patient follow-up: {97.9% for vital status}† (intention-to-treat analysis).
Main results {Overall, apixaban reduced stroke or systemic embolism, all-cause mortality, and major bleeding compared with warfarin.}† All outApixaban vs warfarin in atrial fibrillation‡ Outcomes Stroke or systemic embolism
Major bleeding
All-cause mortality
Age group
Event rates (%/y) Apixaban Warfarin
comes increased with patient age; the benefits of apixaban compared with warfarin did not differ by patient age group (Table).
Conclusion In patients with atrial fibrillation, apixaban reduced stroke or systemic embolism, all-cause mortality, and major bleeding compared with warfarin, regardless of patient age. *See Glossary. †Apixaban reduced stroke and systemic embolism compared with warfarin in atrial fibrillation [Abstract]. Ann Intern Med. 2012;156:JC1-2. Abstract of: Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92.
Sources of funding: Bristol-Myers Squibb and Pfizer. For correspondence: Dr. S. Halvorsen, Oslo University Hospital, Oslo, Norway. E-mail [email protected]. ■
Commentary Elderly persons are more likely to have AF, strokes in the setting of AF, and bleeding during anticoagulation therapy (1). Studies show consistently low rates of anticoagulation in the elderly, and although difficulties in monitoring and uncertainties about efficacy may explain underuse of anticoagulants, fear of hemorrhage seems to be an important factor (2). Halvorsen and colleagues found that the benefits of apixaban over warfarin for efficacy and safety are not affected by age. This finding should allay physician concerns about use of apixaban in older patients. What can we say about other non–vitamin K oral anticoagulants? Bleeding risk increased with age for both rivaroxaban and warfarin in ROCKET-AF, but risks were similar for each treatment across age strata (3). In RE-LY, patients ≥ 75 years of age had similar rates of extracranial bleeding with dabigatran, 110 mg twice daily, and a trend toward higher risk for major bleeding with dabigatran, 150 mg twice daily, compared with warfarin. Intracranial bleeding was reduced with both doses of dabigatran in all age groups (4).
Non–vitamin K oral anticoagulants have advantages in older persons, including ease of use and a lower risk for intracranial hemorrhage. Physicians should evaluate patient comorbid conditions, At a median 1.8 y concomitant medications, and cognition to RRI/RRR (95% CI)§ NNT (CI) minimize bleeding risks.
< 65 y
1.00%
0.86%
RRI 16% (−23 to 72)
Not significant
65 to < 75 y
1.25%
1.73%
RRR 28% (4 to 46)
114 (69 to 797)
≥ 75 y
1.56%
2.19%
RRR 29% (5 to 47)
< 65 y
1.17%
1.51%
RRR 22% (−11 to 45)
Not significant
65 to < 75 y
1.99%
2.82%
RRR 29% (11 to 43)
75 (49 to 196)
≥ 75 y
3.33%
5.19%
RRR 35% (20 to 47)
36 (27 to 62)
< 65 y
2.74%
2.56%
65 to < 75 y
2.67%
3.46%
≥ 75 y
5.42%
5.97%
RRI 6.8% (−16 to 34) RRR 22% (6 to 35) RRR 8.5% (−7 to 22)
91 (56 to 530)
Not significant 69 (44 to 264) Not significant
‡Abbreviations defined in Glossary. RRI, RRR, NNT, and CI calculated from hazard ratios and control event rates in article or provided by author. §Treatment by continuous age interaction: stroke or systemic embolism, P = 0.11; major bleeding, P = 0.63; and all-cause mortality, P = 0.43.
17 June 2014 | ACP Journal Club | Volume 160 • Number 12
Mukul Sharma, MD Kanjana Perera, MD McMaster University Hamilton, Ontario, Canada References 1. Sellers MB, Newby LK. Am Heart J. 2011;161: 241-6. 2. Gross CP, Vogel EW, Dhond AJ, et al. Clin Ther. 2003;25:1750-64. 3. Goodman SG, Wojdyla DM, Piccini JP, et al; ROCKET AF Investigators. J Am Coll Cardiol. 2014;63:891-900. 4. Eikelboom JW, Wallentin L, Connolly SJ, et al. Circulation. 2011;123:2363-72.
© 2014 American College of Physicians
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930364/ by a Tufts University User on 07/28/2017
JC7
